The present invention relates to novel decahydro-isoquinoline derivatives, their preparation, their use as pharmaceuticals and pharmaceutical compositions containing them.
More particularly the invention provides a compound of formula I 
wherein R is hydrogen or (C1-4)alkyl and A and B, independently, are groups of formula (a), (b), (c), (d) or (e) 
wherein
X, X1 and X2, independently, are xe2x80x94CR1xe2x95x90 or xe2x80x94N=
Y is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94NHxe2x80x94
R1 and Rxe2x80x21, independently, are hydrogen, (C1-4)alkyl or (C1-4)alkoxy,
R2 is hydrogen, (C1-4)alkyl, (C1-4)alkoxy, (C1-4)alkoxycarbonyl or halogen, and
R3 and R4, independently, are hydrogen, nitro, cyano, trifluoromethyl, (C1-4)alkyl, (C1-4) alkoxy, (C1-4)alkoxycarbonyl or (C1-4)alkanoyl,
in free base or acid addition salt form.
On account of the asymmetrical carbon atoms which are present in the compounds of formula I and their salts, the compounds may appear in optically active form or in form of mixtures of optical isomers, e.g. in form of racemic mixtures. All optical isomers and their mixtures including the racemic mixtures are part of the present invention.
Halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine. The above-defined alkyl and alkoxy groups preferably represent methyl and methoxy.
In a further aspect, the invention provides a process for the production of the compounds of formula I and their salts, whereby a compound of formula II 
wherein B is as defined above, is reacted with a compound of formula III 
wherein A and R are as defined above, and the compounds of formula I thus obtained are recovered in free base or acid addition salt form.
The reaction can be effected according to known amine formation methods.
Working up the reaction mixtures according to the above process and purification of the compounds thus obtained may be carried out in accordance to known procedures.
Acid addition salts may be produced from the free bases in known manner and vice-versa
The compounds of formula II may be produced from known compounds using conventional procedures, for example by amidation of a compound of formula IV 
wherein B is as defined above, with tert.-butoxycarbonyl-octahydro-isoquinoline-4-carboxylic acid, which can be prepared from isoquinoline-4-carboxylic acid ethyl ester, e.g. as described in Example 1, steps b) to e).
The compounds of formula III may be produced in conventional manner from compounds of formula V 
wherein A and R are as defined above, e.g. as described in Example 1, steps h) and i).
The compounds of formula V may be produced in conventional manner, e.g. from compounds of formulae VI and VII 
wherein A and R are as defined above, as described in Example 1, steps f) and g) or from compounds of formulae VIII and IX 
wherein A and R are as defined above. A resulting compound of formula V may be converted into another compound of formula V e.g. as described in Example 1, step h).
The starting compounds of formulae IV, VI and VII are known or may be produced in analogous manner to known compounds.
Compounds of formula I and their pharmaceutically acceptable acid addition salts, hereinafter referred to as agents of the invention, exhibit valuable pharmacological properties when tested in vitro using somatostatin (somatotropin release inhibiting factor, SRIF) receptor expressing cell cultures and in animals, and are therefore useful as pharmaceuticals.
In particular the agents of the invention show high affinity to somatostatin receptors. More particularly they are selective antagonists at Somatostatin sst3 receptors, previously called SSTR-3 receptors (see Hoyer et al., TIPS, 1995, 16; 86-88), as determined in radioligand binding and second messenger studies [see for example K. Kaupmain et al., FEBS LETTERS 1993, 331: 53-59, S. Siehler et al. Naunyn Schmiedeberg""s Arch Pharmacol, 1999, 360: 488-499] where they exhibit selective affinity for sst3 receptors with pKd values between about 7.5 and 9.0.
The agents of the invention are therefore useful for treatment in anxiety, depression, social phobia, panic disorders, post traumatic stress disorders, ADHD (attention deficit and hyperactivity disorders), bipolar disorders, schizophrenia, including negative symptoms, neurodegenerative diseases such as learning/memory disorders, dementia, age associated memory impairment, SDAT, for the treatment of tumours and for vascular disorders and immunological diseases, as confirm in a range of standard tests as indicated below:
At doses of about 0.3 to 3 mg/kg p.o., the agents of the invention increase exploratory behaviour of mice in the open half of the half enclosed platform, a model which is predictable for anxiolytic activity (Psychopharmacology, 1986, 89:31-37).
In the same half enclosed platform model, the agents of the invention at the above indicated doses also increase vigilance of the mice. The compounds are therefore indicated for the treatment of depression, schizophrenia and dementia, in particular of senile dementia of the Alzheimer type (SDAT).
In the intruder mouse test [Triangle, 1982, 21: 95-105; J. Clin. Psychiatry, 1994, 55:9 (suppl. B) 4-7], the agents of the invention increase social investigation and reduce defensive ambivalence in the treated intruder mouse at doses of about 1 to about 10 mg/kg s.c., suggesting an antimanic profile like carbamazepine and lithium, a neuroleptic profile like clozapine and an anxiolytic profile like diazepam.
In the stress-induced hyperthermia- and the elevated plus-maze paradigm in mice [Lecci et al., Psychopharmacology 101:255-261 (1990) and Rodgers R. J. Behav. Pharmacol. 8: 477-496 (1998), respectively] the agents of the invention reduced the increase in body-temperature and increased the time spent on the open arms, respectively. They are therefore indicated for the treatment of anxiety disorders and panic disorders.
Futhermore at said doses the agents of the invention (given acutely) increase aggressive behaviour (attacks, chases, bites) in the Matched Pairs Situation test in mice [Dixon et al., J. Clin. Psychiatry 55: (9) [Suppl. B] 4-7 (1994)]. Since as mentioned above they additionally attenuate defensive behaviours in the intruder mouse test, the agents of the invention exhibit an ethopharmacological profile which is very similar to that of clozapine and to some extent to that of antimanic agents (Lithium, carbamazepine, valproate). They are therefore indicated for the treatment of affective disorders including bipolar disorders e.g. manic-depressive psychoses, extreme psychotic states e.g. mania, schizophrenia, and excessive mood swings where behavioural stabilisation is desired. In addition, the compounds are indicated in anxiety states, generalised anxiety as well as social stress and agoraphobia, as well as those behavioural states characterised by social withdrawal e.g. negative symptoms [Dixon AK Brit.J.Med.Psychol. 71:,417-445, Dixon AK Fisch HU Neuroscience and Biobehavioural Reviews. 23 (1990) 345-358] and post traumatic stress disorders.
Moreover when given at doses of about 0.03 to 3 mg/kg p.o. to rodents, the agents of the invention counteract electroshock-induced amnesia, increase retention performance in a passive avoidance paradigm (Mondadori et. al., Pharmacology Communications 1992, 2: 93-97) and improve social recoin (Mondadori et al., Behavioural Brain Research 1996, 77: 227-229). The compounds are therefore indicated for the tent of cognitive disturbances and learning/memory disorders.
The positive effects on memory acquisition/retention combined with the sociotropic components displayed by the agents of the invention, suggest that these will prove useful in the treatment of ADHD and various types of dementias, including Alzheimer""s disease.
The agents of the invention are also effective in the treatment of various kinds of tumours, particularly of sst3 receptor bearing tumours, as indicated in proliferation tests with various different cancer cell lines and in tumour growth experiments in nude mice with hormone dependent tumours [see for example: G. Weckbecker et al., Cancer Research 1994, 54: 6334-6337]. Thus, the compounds are indicated in the treatment of, for example, cancers of the breast, the prostate, the colon, the pancreas, the brain and the lung (small cell lung cancer) and for in vivo imaging of sst3 receptor bearing tumours.
For all the above mentioned indications, the appropriate dosage will of course vary depending upon, for example, the compound employed, the host, the mode of administration and the nature and severity of the condition being treated. However, in general satisfactory results in animals are indicated to be obtained at a daily dosage of from about 0.1 to about 10 mg/kg animal body weight. In larger mammals, for example h an indicated daily dosage is in the range from about 5 to about 200 mg, preferably about 10 to about 100 mg of the compound conveniently administered in divided doses up to 4 times a day or in sustained release form.
The agents of the invention may be administered in free form or in pharmaceutically acceptable salt form. Such salts may be prepared in conventional manner and exhibit the same order of activity as the free compounds.
Accordingly in a further aspect the present invention provides the agents of the invention for use as pharmaceuticals, more specifically for treatment in the above-mentioned conditions, e.g. schizophrenia, depression, anxiety and bipolar disorders.
The present invention furthermore provides a pharmaceutical composition comprising an agent of the invention in association with at least one pharmaceutically acceptable diluent or carrier. Such compositions may be formulated in conventional manner. Unit dosage forms contain, for example, from about 0.25 to about 50 mg of an agent according to the invention.
Agents of the invention may be administered by any conventional route, for example parenterally e.g. in form of injectable solutions or suspensions, or enterally, preferably orally, e.g. in the form of tablets or capsules.
The preferred indications are schizophrenia (especially negative symptoms and cognitive impairment), depression, anxiety and affective disorders, including bipolar disorders, e.g. mania.
The preferred compound is the compound of example 32. With reference to the above-mentioned tests, in the intruder mouse this compound at doses of 0.3, 1 and 3 mg/kg p.o. increases attention and social exploration and reduces defensive ambivalence and arrested flight. In the social recognition test it increases memory at doses of 0.03 to 30 mg/kg p.o. It also reduces stress-induced hypothermia in mice at doses of 0.3 to 10 mg/kg p.o.
In accordance with the foregoing, the present invention also provides the use of an agent of the invention as a pharmaceutical, e.g. for the treatment of schizophrenia, depression, anxiety and bipolar disorders.
Moreover the present invention provides the use of an agent of the invention for the manufacture of a medicament for the treatment of any condition mentioned above, e.g. schizophrenia, depression, anxiety and affective disorders.
In still a further aspect the present invention provides a method for the treatment of any condition mentioned above, e.g. schizophrenia, depression, anxiety and bipolar disorders, in a subject in need of such treatment, which comprises administering to such subject a therapeutically effective amount of an agent of the invention.